High Or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride And Nab-paclitaxel In Treating Patients With Pancreatic Cancer That Cannot Be Removed By Surgery

Study Overview

High or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride and Nab-paclitaxel in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery

This randomized phase II trial studies how well high or standard intensity radiochemotherapy after gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) work compared with gemcitabine hydrochloride and nab-paclitaxel alone in treating patients with pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Giving radiation therapy in different ways and adding chemotherapy may kill more tumor cells. It is not yet known whether high intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel is more effective than standard intensity radiochemotherapy after gemcitabine hydrochloride and nab-paclitaxel or gemcitabine hydrochloride and nab-paclitaxel alone in treating pancreatic cancer.

PRIMARY OBJECTIVES: * I. To determine if intensified radiochemotherapy following gemcitabine and nab-paclitaxel in patients with unresectable pancreatic cancer will show a signal for improved 2-year overall survival (OS) from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone. * II. To determine if standard radiochemotherapy, following gemcitabine and nab-paclitaxel, in patients with unresectable pancreatic cancer will show a signal for improved 2-year OS from 10% to 22.5% as compared to chemotherapy with gemcitabine and nab-paclitaxel alone. SECONDARY OBJECTIVES: * I. To evaluate patterns of failure (local and systemic progression) by SMAD family member 4 (SMAD4) status and intensity of radiation therapy. * II. To evaluate the impact of radiochemotherapy on OS for the subset of SMAD4 intact patients. * III. To evaluate adverse events associated with the treatments. * IV. To evaluate correlation between SMAD4 status determined by immunohistochemistry (IHC) and genetic SMAD4 status. Patients are randomized to 1 of 3 treatment arms. After completion of study treatment, patients are followed up at 1 month and then every 3 months.

Pancreatic Adenocarcinoma
Stage III Pancreatic Cancer

RADIATION: low intensity radiation therapy
DRUG: Capecitabine
DRUG: Gemcitabine
RADIATION: high intensity radiation therapy
DRUG: nab-Paclitaxel

RTOG 1201
NCI-2013-01280 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
RTOG 1201 (OTHER Identifier) (OTHER: NRG Oncology)
RTOG-1201 (OTHER Identifier) (OTHER: CTEP)
U10CA180868 (U.S. NIH Grant/Contract)
U10CA021661 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2013-08-09	Results First Submitted 2017-10-06	Last Update Submitted that met QC Criteria 2018-06-14
First Submitted that Met QC Criteria 2013-08-09	Results First Submitted that Met QC Criteria 2018-03-21	Last Update Posted (ACTUAL) 2018-07-13
First Posted (ACTUAL) 2013-08-13	Results First Posted 2018-03-22	Last Verified 2018-06

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Chemotherapy + high intensity radiation Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent high intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with ge	DRUG: Capecitabine 825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy. DRUG: Gemcitabine 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks] RADIATION: high intensity radiation therapy 63 Gy intensity-modulated radiation therapy (IMRT) in 28 2.25 Gy fractions, 5 days/week, starts 3-5 weeks after the last dose of induction chemotherapy DRUG: nab-Paclitaxel 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]
EXPERIMENTAL: Chemotherapy + low intensity radiation Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent low intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with gem	RADIATION: low intensity radiation therapy 50.4 Gy in 28 1.8 Gy fractions (IMRT or 3D-CRT), 5 days/week, starting 3-5 weeks after the last dose of induction chemotherapy DRUG: Capecitabine 825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy. DRUG: Gemcitabine 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks] DRUG: nab-Paclitaxel 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]
ACTIVE_COMPARATOR: Chemotherapy Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]	RADIATION: low intensity radiation therapy 50.4 Gy in 28 1.8 Gy fractions (IMRT or 3D-CRT), 5 days/week, starting 3-5 weeks after the last dose of induction chemotherapy DRUG: Capecitabine 825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy. DRUG: Gemcitabine 1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks] RADIATION: high intensity radiation therapy 63 Gy intensity-modulated radiation therapy (IMRT) in 28 2.25 Gy fractions, 5 days/week, starts 3-5 weeks after the last dose of induction chemotherapy DRUG: nab-Paclitaxel 125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Chemotherapy + high intensity radiation

Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent high intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with ge

DRUG: Capecitabine

825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy.

DRUG: Gemcitabine

1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]

RADIATION: high intensity radiation therapy

63 Gy intensity-modulated radiation therapy (IMRT) in 28 2.25 Gy fractions, 5 days/week, starts 3-5 weeks after the last dose of induction chemotherapy

DRUG: nab-Paclitaxel

125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]

EXPERIMENTAL: Chemotherapy + low intensity radiation

Induction chemotherapy with four cycles of gemcitabine and nab-paclitaxel [randomized to this arm after 3rd cycle and no progression]; followed by concurrent low intensity radiation therapy and capecitabine; followed by consolidation chemotherapy with gem

RADIATION: low intensity radiation therapy

50.4 Gy in 28 1.8 Gy fractions (IMRT or 3D-CRT), 5 days/week, starting 3-5 weeks after the last dose of induction chemotherapy

DRUG: Capecitabine

825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy.

DRUG: Gemcitabine

1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]

DRUG: nab-Paclitaxel

125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]

ACTIVE_COMPARATOR: Chemotherapy

Gemcitabine and nab-paclitaxel until progression or unacceptable toxicity [randomized to this arm after 3rd cycle and no progression]

RADIATION: low intensity radiation therapy

50.4 Gy in 28 1.8 Gy fractions (IMRT or 3D-CRT), 5 days/week, starting 3-5 weeks after the last dose of induction chemotherapy

DRUG: Capecitabine

825 mg/m2 PO twice daily, 5 days/week, beginning on the first day of radiation therapy and ending on the last day of radiation therapy.

DRUG: Gemcitabine

1000 mg/m2 weekly as a 30 minute infusion after nab-Paclitaxel, three weeks on and 1 week off [1 cycle = 4 weeks]

RADIATION: high intensity radiation therapy

63 Gy intensity-modulated radiation therapy (IMRT) in 28 2.25 Gy fractions, 5 days/week, starts 3-5 weeks after the last dose of induction chemotherapy

DRUG: nab-Paclitaxel

125 mg/m2 weekly as a 30-40 minute infusion, three weeks on and 1 week [1 cycle = 4 weeks]

Primary Outcome Measures	Measure Description	Time Frame
Overall Survival	Survival time is defined as time from randomization to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported.	From randomization until last follow-up. Analysis was to occur after a total of 140 deaths were reported within the pairing of each radiation arm with the chemotherapy alone arm. Maximum follow-up at time of study termination was 8.3 months.

Secondary Outcome Measures	Measure Description	Time Frame
Overall Survival Within SMAD4 Subsets	Survival time is defined as time from randomization to date of death from any cause and was to be estimated by the Kaplan-Meier method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients last reported to be alive at time of study termination is reported. Patients are categorized by SMAD4 status of "intact" (positive nuclear labeling is observed of the neoplastic cells ), "loss" (no labeling observed of the neoplastic cells) , or "undetermined" (insufficient material for immunostaining or results are equivocal). This study terminated early with only 20 registered (346 planned) and 13 randomized (288 planned). There are no proven results as to which category has better incomes, but this study hypothesizes that "intact" is highly correlated with local failures and "loss" is highly correlated with widespread metastasis, in which case "intact" would correspond with positive results relative to "loss".	From randomization until last follow-up. Analysis was to occur after a total of 140 deaths were reported within the pairing of each radiation arm with the chemotherapy alone arm. Maximum follow-up at time of study termination was 8.3 months.
Patterns of Failure (Local and Metastatic Failure)	Local progression is defined as least a 20% increase in the sum of diameters of the primary, taking as reference the baseline sum. Given the inherent inaccuracy in determining size of a primary pancreatic carcinoma, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and progression must be demonstrated on at least two sequential scans. Metastatic failure is defined as metastatic disease. Local and distant failure were to be estimated by the cumulative incidence method. Given the limited follow-up due to early closure and termination of data collection, only the number of patients with failure is reported.	From randomization until last follow-up. Maximum follow-up at time of study termination was 8.3 months.
Correlation Between SMAD4 Status Determined by Immunohistochemistry (IHC) and Genetic SMAD4 Status		Baseline

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

History/physical examination within 30 days prior to registration
Whole body fluorodeoxyglucose-positron emission tomography/computerized tomography (FDG-PET/CT) within 30 days prior to registration NOTE: If whole-body FDG-PET/CT is not performed, CT of the chest and CT (or MRI) of abdomen and pelvis must be obtained (imaging of abdomen and pelvis need not be repeated if already included in pancreas protocol study) 6. Zubrod Performance Status 0-1 within 30 days prior to registration 7. Age ≥ 18; 8. Complete blood count (CBC)/differential obtained within 14 days prior to step 1 registration, with adequate bone marrow function defined as follows:

Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
Platelets ≥ 100,000 cells/mm3
Hemoglobin ≥ 8.0 g/dl (NOTE: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable) 9. Additional laboratory studies within 14 days prior to registration:

carbohydrate antigen 19-9 (CA19-9); NOTE: in the event that a stent has been placed and biliary obstruction has been relieved, the CA19-9 should be drawn post stent placement
Creatinine < 2 mg/dl; Glomerular filtration rate (GFR) > 50 mL/min (Cockroft and Gault formula)
Bilirubin < 1.5 x ULN
Alanine aminotransferase (ALT) and aminotransferase (AST) ≤ 2.5 x ULN
Activated partial thromboplastin time (aPTT), prothrombin time (PT) ≤1.2 x upper limit of normal (ULN) 10. Patient must provide study specific informed consent prior to study entry 11. Women of childbearing potential and male participants must practice adequate contraception during protocol treatment and for at least 6 months following treatment 12. For females of child-bearing potential, negative serum pregnancy test within 30 days prior to registration

Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
Transmural myocardial infarction within the last 6 months
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients 6. Pregnancy or women of childbearing potential, women who cannot discontinue breastfeeding and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic 7. Prior allergic reaction to the study drug(s) involved in this protocol 8. Pre-existing Grade 2 or greater neuropathy 9. Distant metastases

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

National Cancer Institute (NCI)
NRG Oncology

Investigators

PRINCIPAL_INVESTIGATOR: Edgar Ben-Josef, NRG Oncology

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Jani A, Horowitz DP. Radiation Therapy Deviations in Trial of Locally Advanced Pancreatic Cancer [corrected]. JAMA. 2016 Oct 4;316(13):1409. doi: 10.1001/jama.2016.9778. No abstract available. Erratum In: JAMA. 2016 Nov 8;316(18):1924. doi: 10.1001/jama.2016.17038.

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